Small Molecules Still Leading in New Drug Approvals

By Patricia Van Arnum - DCAT Editorial Director

February 6, 2019

Small molecules accounted for 42, or 71%, of the 59 new molecule entities (NMEs) approved by the FDA in 2018, continuing a recent trend in which small molecules have accounted for roughly three-quarters of NME approvals. Which small-molecules and companies contributed to the NME Class of 2018?

Small molecules leading the NME pack

In 2018, the US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) approved a record-high 59 new molecular entities (NMEs), surpassing the previous record of 53 NME approvals in 1996 and the 46 NMEs approved in 2017. Small molecules dominated in NME approvals in 2018 with 42 (71% of NME approvals) compared to 17 biologic-based NME approvals (29% of NME approvals), which included one antibody drug conjugate (ADC) (see Table I at end of article; NDA approval denotes small molecule)

This product mix in 2018 is consistent with NME approvals in 2017 and with recent years with the exception of 2016. In 2017, small-molecule NME approvals accounted for 74% of new drug approvals (see Table II at end of article) and biologics 26%. Between 2010 and 2015, small molecules accounted for between 71% and 81% of NME approvals. The exception was in 2016, when a lower number of NME approvals occurred with 22 NME approvals, which included 13 small-molecule NME approvals or 59%.

Big Pharma and small molecules

Of the 42 small-molecule NME approvals in 2018, 18 or 43% were from the large pharmaceutical companies, and 57% of small-molecule approvals in 2018 were from small to mid-sized companies (see Table I at end of article; NDA approval denotes small molecule).

Among the large pharmaceutical companies, Pfizer led with four NME approvals in 2018, all of which were small molecules. These were: Daurismo (glasdegib) for treating newly diagnosed acute myeloid leukemia (AML) in adult patients; Lorbrena (loratinib) for treating patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; Talzenna (talazoparib) for treating locally advanced or metastatic breast cancer patients with a germline BRCA mutation; and Vizimpro (dacomitinib) for treating metastatic non-small-cell lung cancer.

Fourteen of the large pharmaceutical companies each had one small-molecule NME approval in 2018.

AbbVie received approval for Orilissa (elagolix sodium) for treating moderate-to-severe pain associated with endometriosis. Allergan got the FDA nod for Seysara (sarecycline) for treating inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients nine years of age and older. Astellas received approval for Xospata (gilteritinib) for treating relapsed or refractory acute myeloid leukemia, and AstraZeneca received approval for Lokelma (sodium zirconium cyclosilicate) for treating hyperkalemia (high potassium levels). Eli Lilly and Company got the FDA nod for Olumiant (baricitinib) for treating moderately to severely active rheumatoid arthritis. Also, through its pending $8-billion acquisition of Loxo Oncology, Lilly will gain another small-molecule NME approval from 2018, Vitrakvi (larotrectinib), an anti-cancer drug.

Mylan, although largely a generic-drug company, did get a NME approval in 2018, for its small-molecule, Yupelri (revefenacin) for treating chronic obstructive pulmonary disease (COPD). Novartis, through its acquisition of Advanced Accelerator Applications in 2018, received approval for the radiopharmaceutical, Lutathera (lutetium Lu 177 dotatate) for treating gastroenteropancreatic neuroendocrine tumors, a type of cancer that affects the pancreas or gastrointestinal tract.

Shire, which was acquired by Takeda in January 2019, received approval for Motegrity (prucalopride) for treating idiopathic constipation. Shionogi received approval for Mulpleta (lusutrombopag) for treating thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure, and Roche's Genentech received approval for Xofluza (baloxavir marboxil), an antiviral medicine.

Table I: Approvals of New Molecular Entities, New Drug Applications (NDAs) and Original Biologics License Applications (BLAs) by the US Food and Drug Administration’s Center in 2018.

Company

Brand name (active ingredient); application type

Indication

AbbVie

Orilissa (elagolix sodium); NDA

Moderate-to-severe pain associated with endometriosis

Advanced Accelerator Applications (Novartis company)

Lutathera (lutetium Lu 177 dotatate); NDA

Gastroenteropancreatic neuroendocrine tumors, a type of cancer that affects the pancreas or gastrointestinal tract

Achaogen

Zemdri (plazomicin); NDA

Adults with complicated urinary tract infections

Agios Pharmaceuticals

Tibsovo (ivosidenib); NDA

Relapsed or refractory acute myeloid leukemia

AkaRx

Doptelet (avatrombopag); NDA

Low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure

To treat adults and children ages 1 year and older with x-linked hypophosphatemia, a rare, inherited form of rickets

US WorldMeds

Lucemyra (lofexidine); NDA

Non-opioid treatment for management of opioid withdrawal symptoms in adults

Vertex Pharmaceuticals

Symdeko (tezacaftor and ivacaftor); NDA

Cystic fibrosis in patients age 12 years and older

Novartis acquired Advanced Accelerator Applications in January 2018.

Paratek Pharmaceuticals has exclusively licensed US development and commercialization rights of Seysara for the treatment of acne to Allergan, which has assigned such rights to Almirall SA. Paratek retains development and commercialization rights in the rest of the world.

In August 2015, Amgen entered into a global collaboration with Novartis to jointly develop and commercialize treatments in the fields of migraine and Alzheimer's disease. The collaboration focuses on investigational Amgen drugs in the migraine field, including Aimovig. In April 2017, the collaboration was expanded to include co-commercialization of Aimovig in the US. For the migraine program, Amgen retains exclusive rights in Japan, and Novartis has exclusive rights in Europe, Canada, and rest of the world.

Array BioPharma has exclusive rights to Braftovi (encorafenib) and Mektovi (binimetinib) in the US and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including in Europe, Asia, and Latin America.

Eli Lilly and Company agreed to acquire Loxo Oncology in 2018.

Shire was acquired by Takeda in January 2018.

Sun Pharmaceutical Industries Ltd.'s wholly owned subsidiary licensed worldwide rights to Ilumya (tildrakizumab) from a subsidiary of Merck & Co., Inc. in 2014. Funded by a Sun Pharma subsidiary, Merck & Co., Inc. was responsible for the completion of Phase-III trials and submission of a biologics license application to the US Food and Drug Administration (FDA) as well as manufacturing finished goods to support Sun Pharma's initial product launch. Sun Pharma is responsible for all post-approval regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing, and commercialization of the approved product. Sun Pharma is also responsible for all regulatory, pharmacovigilance, post approval studies, manufacturing, and commercialization of approved products for all non-U.S. markets. Merck & Co is eligible to receive milestone payments and royalties on sales of Ilumya.

Source: US Food and Drug Administration's Center for Drug Evaluation and Research and company information.

Table II: Small Molecule and Biologics New Molecular Entities Approved by the US Food and Drug Administration’s Center for Drug Evaluation and Research, 2010 to 2018.

Year

Number of New Molecular Entities (NMEs) Approved

Percentage relative to total NME approvals and number of small molecules and biologics approved as NMEs

n 2015, 32 small-molecule drugs were approved as NDAs and one insulin analog, Novo Nordisk's Tresiba (insulin degludec injection), a long-acting basal human insulin analog produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification was approved as a NDA, not as a biologics license application.